Genetic Variant EPAS1:c.27-17667G>A (chr2-46329206-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001430.5(EPAS1):c.27-17667G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,168 control chromosomes in the GnomAD database, including 1,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 1517 hom., cov: 32)

Consequence

EPAS1
NM_001430.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.188

Publications

31 publications found

Variant links:

Genes affected

EPAS1 (HGNC:3374): (endothelial PAS domain protein 1) This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]

EPAS1 Gene-Disease associations (from GenCC):

erythrocytosis, familial, 4
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal dominant secondary polycythemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPAS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPAS1	NM_001430.5 link	c.27-17667G>A		intron_variant	Intron 1 of 15	ENST00000263734.5	NP_001421.2	Q99814B3KW07
EPAS1	XM_011532698.3 link	c.65+3330G>A		intron_variant	Intron 1 of 15		XP_011531000.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPAS1	ENST00000263734.5 link	c.27-17667G>A	intron_variant	Intron 1 of 15	1	NM_001430.5	ENSP00000263734.3	Q99814
EPAS1	ENST00000449347.5 link	c.27-17667G>A	intron_variant	Intron 2 of 6	3		ENSP00000406137.1	C9J9N2
EPAS1	ENST00000460015.1 link	n.433-17667G>A	intron_variant	Intron 1 of 1	4
EPAS1	ENST00000467888.5 link	n.175-17667G>A	intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15438

AN:

152050

Hom.:

1519

Cov.:

show subpopulations

Gnomad AFR

AF:

0.234

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0726

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.0595

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0226

Gnomad OTH

AF:

0.0736

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.102

AC:

15458

AN:

152168

Hom.:

1517

Cov.:

AF XY:

0.105

AC XY:

7826

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.234

AC:

9692

AN:

41462

American (AMR)

AF:

0.0486

AC:

744

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0726

AC:

252

AN:

3470

East Asian (EAS)

AF:

0.294

AC:

1518

AN:

5170

South Asian (SAS)

AF:

0.170

AC:

820

AN:

4824

European-Finnish (FIN)

AF:

0.0595

AC:

631

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0226

AC:

1536

AN:

68010

Other (OTH)

AF:

0.0733

AC:

155

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

634

1268

1901

2535

3169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0429

Hom.:

181

Bravo

AF:

0.107

Asia WGS

AF:

0.212

AC:

739

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.1

(source)

DANN

Benign

0.60

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over